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- Mechanism of urine formation PH1.24
- Diuretics PH1.24
- Antidiuretics PH1.24
Book Chapter
Renal pharmacology - Pharmacology for Medical Graduates, 4th Updated Edition
Pharmacology for Medical Graduates, 4th Updated Edition, CHAPTER 4, 151-163
Kidney is mainly a regulatory organ; it also has excretory function. The functional unit of kidney is nephron. Each kidney contains about 1 million nephrons. The functions of kidney are as follows:
- 1.
Regulatory: Acid–base, fluid and electrolyte balance.
- 2.
Excretory: Excretion of nitrogenous waste products.
- 3.
Hormonal: Activation of vitamin D, production of renin and erythropoietin.
Mechanism of urine formation PH1.24
It consists of the following steps
- 1.
Glomerular filtration
- 2.
Tubular reabsorption
- 3.
Active tubular secretion
Urine formation begins with glomerular filtration. The volume of fluid filtered is about 180 L/day, of which more than 99% gets reabsorbed in the renal tubules; urine output is about 1–1.5 L/day. After filtration, fluid traverses in the renal tubules. The tubular fluid contains Na + , K + , Cl − , HCO 3 − , amino acids, glucose, etc.
Proximal convoluted tubule: Site 1 ( fig. 4.1 )
Most of the filtered Na + is actively reabsorbed; chloride is reabsorbed passively along with sodium. Carbonic anhydrase plays an important role in the reabsorption of bicarbonate and secretion of H + . The Na + –H + exchanger in the proximal tubular cells transports Na + from the lumen into the cell and H + from the cell into the tubular fluid. Potassium, glucose, amino acids, etc. are also reabsorbed in proximal convoluted tubule (PCT). Proportionately, water also gets reabsorbed, so tubular fluid in the PCT remains isotonic.
Descending limb of loop of henle
The descending limb is impermeable to Na + and urea and highly permeable to water. Hence, fluid in this segment becomes hypertonic.
Thick ascending limb of loop of henle: Site 2 ( fig. 4.1 )
The thick ascending limb is impermeable to water but highly permeable to Na + and Cl − . Active reabsorption of sodium and chloride occurs by Na + –K + –2Cl − cotransporter. This is selectively blocked by loop diuretics. Ca 2+ and Mg 2+ are also reabsorbed at this site. The tubular fluid becomes hypotonic.
Early distal tubule: Site 3 ( fig. 4.1 )
It is impermeable to water, but sodium and chloride are reabsorbed with the help of Na + –Cl − symporter. This is blocked by thiazides.
Late distal tubule and collecting duct: Site 4 ( fig. 4.1 )
Sodium is actively reabsorbed; chloride and water diffuse passively. Exchange of Na + –K + , H + ions occur. The Na + –K + exchange is under the influence of aldosterone (aldosterone promotes Na + absorption and K + depletion). Absorption of water in collecting duct (CD) is under the influence of antidiuretic hormone (ADH). In the absence of ADH, the CD becomes impermeable to water and a large amount of dilute urine is excreted. Normally, H + ions present in urine convert NH 3 to NH 4 + , which is excreted.
Diuretics PH1.24
Diuretics are drugs that promote excretion of Na + and water in urine.
Classification according to primary site of action in the nephron ( fig. 4.1 )
- 1.
Drugs acting at PCT (site 1)
Carbonic anhydrase inhibitor: Acetazolamide.
- 2.
Drugs acting at thick ascending limb of loop of Henle (site 2)
Loop diuretics: Furosemide, bumetanide, torsemide.
- 3.
Drugs acting at early distal tubule (site 3)
Thiazides: Chlorothiazide, hydrochlorothiazide, hydroflumethiazide, bendroflumethiazide, benzthiazide.
Thiazide-related diuretics: Chlorthalidone, indapamide, metolazone, xipamide.
- 4.
Drugs acting at late distal tubule and CD (site 4)
Aldosterone antagonists: Spironolactone, eplerenone.
Direct inhibitors of renal epithelial Na + channels: Amiloride, triamterene.
- 5.
Drugs acting on entire nephron (main site of action is loop of Henle)
Osmotic diuretics: Mannitol, glycerol, isosorbide.
Carbonic anhydrase inhibitors
Mechanism of action.
CO 2 and H 2 O from the tubular lumen diffuse into tubular cell where H 2 CO 3 is formed under the influence of carbonic anhydrase ( Fig. 4.2 ). Carbonic acid (H 2 CO 3 ) dissociates into H + and HCO 3 − . The bicarbonate ions are transported into the interstitium. The H + ions exchange with luminal Na + (Na + –H + antiporter). In the lumen, H + ions combine with the filtered HCO 3 − to form H 2 CO 3 . The H 2 CO 3 dissociates into CO 2 and H 2 O with the help of carbonic anhydrase, which is present near the brush border. The main site of action of acetazolamide is proximal tubule (site 1); it also acts in the CD. Acetazolamide, by inhibiting carbonic anhydrase enzyme, prevents the formation of H + ions. Thus, Na + –H + exchange is prevented. Na + is excreted along with HCO 3 − in urine.
In the DCT, increased Na + –K + exchange leads to loss of K + . The net effect is loss of Na + , K + and HCO 3 − in urine resulting in alkaline urine.
Uses.
Acetazolamide is not used as diuretic because of its low efficacy. It is used in the following:
- 1.
Glaucoma: Carbonic anhydrase inhibitors decrease intraocular pressure (IOP) by reducing the formation of aqueous humour. Acetazolamide is used in acute congestive glaucoma by oral and i.v. routes. Topical carbonic anhydrase inhibitors (dorzolamide and brinzolamide) are used in chronic simple glaucoma (see p. 58).
- 2.
To alkalinize urine in acidic drug poisoning.
- 3.
Acute mountain sickness: Acetazolamide can be used both for symptomatic relief and prophylaxis of acute mountain sickness. It is better to administer it prophylactically. The beneficial effect may be due to a decrease in pH and formation of cerebrospinal fluid.
- 4.
Miscellaneous: As an adjuvant in familial periodic paralysis – benefit results from lowering of pH.
Adverse effects.
These include hypersensitivity reactions (skin rashes, fever, nephritis, etc.), drowsiness, paraesthesia, hypokalaemia, metabolic acidosis, headache and renal stones.
Contraindications
- 1.
Liver disease: Hepatic coma may be precipitated in patients with cirrhosis due to decreased excretion of NH 3 in alkaline urine.
- 2.
Chronic obstructive pulmonary disease (COPD): Worsening of metabolic acidosis is seen in patients with COPD.
Osmotic diuretics
These include mannitol, glycerol and isosorbide.
Mannitol: Mannitol is administered intravenously. It is neither metabolized in the body nor significantly reabsorbed from the renal tubules. It is pharmacologically inert and is freely filtered at the glomerulus.
Glycerol: Glycerol can be used orally to reduce IOP in acute congestive glaucoma.
Mechanism of action.
Osmotic diuretics draw water from tissues by osmotic action. This results in increased excretion of water and electrolytes. Their site of action is in the loop of Henle and proximal tubule.
Uses of osmotic diuretics
- 1.
Mannitol is used to reduce the elevated intracranial tension (ICT) following head injury or tumour. It draws fluid from the brain into the circulation by osmotic effect, thus lowering ICT.
- 2.
Mannitol 20% (i.v.), glycerol 50% (oral) and isosorbide (oral) are used to reduce the elevated IOP in acute congestive glaucoma. They draw fluid from the eye, by osmotic effect, into blood – IOP is decreased.
- 3.
Mannitol is used to prevent acute renal shutdown in shock, cardiovascular surgery, haemolytic transfusion reactions, etc.
- 4.
Mannitol is useful to maintain the osmolality of ECF after dialysis.
Adverse effects
- 1.
Too rapid and too much quantity of i.v. mannitol can cause marked expansion of ECF volume which can lead to pulmonary oedema.
- 2.
Headache, nausea and vomiting may occur.
- 3.
Glycerol can cause hyperglycaemia.
Contraindications.
Mannitol is contraindicated in congestive cardiac failure (CCF) and pulmonary oedema because it expands ECF volume by increasing the osmolality of extracellular compartment and increases the load on heart, thus, aggravating the above condition. Other contraindications are chronic oedema, anuric renal disease, active intracranial bleeding and acute tubular necrosis.
Loop diuretics (high-ceiling diuretics)
The important loop diuretics are furosemide, bumetanide and torsemide.
Mechanism of action ( fig. 4.3 ).
Site of action is the thick ascending limb of loop of Henle (site 2). Loop diuretics bind to luminal side of Na + –K + –2Cl − cotransporter and block its function. There is an increased excretion of Na + and Cl − in urine. The tubular fluid reaching DCT contains large amount of Na + . Hence, more Na + exchanges with K + , leading to K + loss. Furosemide has weak carbonic anhydrase–inhibiting activity, hence, increases the excretion of HCO 3 − . Loop diuretics also increase the excretion of Ca 2+ and Mg 2+ .
Loop diuretics are called high-ceiling diuretics because they are highly efficacious – have maximal Na + excreting capacity when compared to thiazides and potassium-sparing diuretics.
The loop diuretics are rapidly absorbed through the gastrointestinal tract. Furosemide and bumetanide are administered by oral, i.v. and i.m. routes. Torsemide is given orally and intramuscularly. Furosemide has a rapid onset of action within 2–5 minutes of i.v.; 10–20 minutes after i.m. and 30–40 minutes after oral administration. The duration of action of furosemide is short (2–4 hours).
Bumetanide and torsemide
- ■
Can be administered orally and parenterally.
- ■
Are more potent than furosemide.
- ■
Have better oral bioavailability than furosemide.
- ■
Torsemide: Longer half-life than others.
Therapeutic uses of loop diuretics
- 1.
During the initial stages of renal and cardiac oedema, loop diuretics are preferred. They are also useful in hepatic oedema – vigorous diuresis should be avoided to prevent hepatic coma.
- 2.
Intravenous furosemide, along with isotonic saline (to prevent volume depletion), is used in hypercalcaemia as it promotes the excretion of Ca 2+ in urine.
- 3.
Acute pulmonary oedema – loop diuretics act in the following way:
- 4.
Loop diuretics may be used in cerebral oedema but i.v. mannitol is the preferred drug.
- 5.
Hypertension: Loop diuretics can be used in hypertension associated with CCF/renal failure and in hypertensive emergencies. Furosemide is not preferred in uncomplicated primary hypertension because of its short duration of action.
- 6.
To prevent volume overload, furosemide is administered during blood transfusion.
Adverse effects of loop diuretics
- 1.
Electrolyte disturbances are the common adverse effects seen with loop diuretics. They are as follows:
- (a)
Hypokalaemia: It is the most important adverse effect. It can cause fatigue, muscular weakness and cardiac arrhythmias. Hypokalaemia can be prevented by using a combination of loop diuretic with potassium-sparing diuretic. It can be treated by K + supplementation.
- (b)
Hyponatraemia: Loop diuretics can cause depletion of sodium from the body.
- (c)
Hypocalcaemia and hypomagnesaemia: These are due to the increased urinary excretion of Ca 2+ and Mg 2+ , respectively. Hypomagnesaemia can predispose to cardiac arrhythmias.
- (a)
- 2.
The metabolic disturbances include:
- (a)
Hyperglycaemia: This can occur due to decreased insulin secretion.
- (b)
Hyperuricaemia: These drugs decrease the renal excretion of uric acid and may precipitate attack of gout.
- (c)
Hyperlipidaemia: They increase plasma triglycerides and LDL cholesterol levels.
- (a)
- 3.
Ototoxicity manifests as deafness, vertigo and tinnitus and is due to damage to hair cells in inner ear. The symptoms are usually reversible on stoppage of therapy. The risk of ototoxicity is increased in patients with renal impairment and in those receiving other ototoxic drugs like cyclosporine and aminoglycosides.
- 4.
Hypersensitivity: Skin rashes, eosinophilia, photosensitivity, etc. may occur.
Drug interactions
- 1.
Furosemide/thiazides × digoxin: These diuretics cause hypokalaemia which increases the binding of digoxin to Na + -K + -ATPase leading to digoxin toxicity.
- 2.
Furosemide × aminoglycosides: Both are ototoxic drugs and cause enhanced toxicity when used together.
- 3.
Furosemide × nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs inhibit PG synthesis and block prostaglandin-mediated haemodynamic changes of loop diuretics. Chronic use of NSAIDs leads to Na + and H 2 O retention and diminish the antihypertensive effect of loop diuretics/thiazides.
- 4.
Furosemide/thiazides × lithium: Diuretics cause hyponatraemia resulting in compensatory increase in reabsorption of sodium and lithium in the PCT leading to lithium toxicity.
- 5.
Furosemide/chlorthalidone × amiloride: Furosemide/chlorthalidone causes hypokalaemia, whereas amiloride conserves potassium. The combination of these diuretics does not alter plasma potassium levels; also improves diuretic response – synergistic effect.
Thiazides (benzothiadiazides) and thiazide-related diuretics
Thiazides are medium-efficacy diuretics.
Mechanism of action.
Thiazides inhibit Na + –Cl − symport in early distal tubule (site 3) and increase Na + and Cl − excretion ( Fig. 4.4 ). There is increased delivery of Na + to late distal tubule. Hence, there is increased exchange of Na + –K + which results in K + loss. Some of the thiazides also have weak carbonic anhydrase inhibitory action and increase HCO 3 − loss. Therefore, there is a net loss of Na + , K + , Cl − , HCO 3 − in urine. Unlike loop diuretics, thiazides decrease Ca 2+ excretion.
Pharmacokinetics.
Thiazides are administered orally. They have long duration of action and are excreted in urine.
Uses
- 1.
Hypertension: Thiazides are used in the treatment of essential hypertension (see p. 104).
- 2.
Oedema: Thiazides are used in combination with loop diuretics in severe CHF. They are not very effective in hepatic oedema. Most thiazides, except metolazone, are not effective when glomerular filtration rate (GFR) is low.
- 3.
Hypercalciuria: Thiazides are used in calcium nephrolithiasis as they reduce the urinary excretion of calcium.
- 4.
Diabetes insipidus (DI) (see p. 163).
Adverse effects
- 1.
Thiazides cause electrolyte disturbances which include hypokalaemia, hyponatraemia, hypomagnesaemia and hypercalcaemia.
- (a)
Hypokalaemia is more common with thiazides than loop diuretics because of their long duration of action.
- (b)
Hypercalcaemia is due to decreased urinary excretion of Ca 2+ .
- (a)
- 2.
The metabolic disturbances are similar to that of loop diuretics – hyperglycaemia, hyperlipidaemia and hyperuricaemia.
- 3.
They may cause impotence; hence, thiazides are not the preferred antihypertensives in young males.
- 4.
Others: Skin rashes, photosensitivity, gastrointestinal disturbances like nausea, vomiting and diarrhoea can occur. Diuretics should be avoided in pregnancy as they reduce placental perfusion by decreasing blood volume which can cause fetal death.
Thiazide-related diuretics
Chlorthalidone is a frequently used thiazide-related diuretic in hypertension as it has a long duration of action. Indapamide and metolazone are longer acting than thiazides. They are used in hypertension. Metolazone and xipamide are also used for treatment of oedema. Metolazone can be used in severe renal failure.
Potassium-sparing diuretics
Aldosterone antagonists
Spironolactone.
Spironolactone is an aldosterone antagonist. It is a synthetic steroid and structurally related to aldosterone.
Aldosterone enters the cell and binds to specific mineralocorticoid receptor (MR) in the cytoplasm of late distal tubule and CD cells (site 4). The hormone receptor complex (MR–AL) enters the cell nucleus, where it induces synthesis of aldosterone-induced proteins (AIPs). The net effect of AIPs is to retain sodium and excrete potassium ( Fig. 4.5 ).
Spironolactone competitively blocks the MR and prevents the formation of AIPs. Therefore, spironolactone promotes Na + excretion and K + retention. Spironolactone is most effective when circulating aldosterone levels are high. It also increases Ca 2+ excretion.
Pharmacokinetics.
Spironolactone is administered orally, gets partly absorbed and is highly bound to plasma proteins; extensively metabolized in liver and forms active metabolite, canrenone, which has a long plasma half-life.
Uses
- 1.
In oedematous conditions associated with secondary hyperaldosteronism (CCF, hepatic cirrhosis and nephrotic syndrome).
- 2.
CCF: Spironolactone is often used in moderate-severe heart failure because it blocks the effects of aldosterone. It prevents hypokalaemia, ventricular remodelling and retards the progression of the disease.
- 3.
Spironolactone is often used with thiazides/loop diuretics: Serum potassium level is maintained and antihypertensive efficacy is enhanced.
- 4.
Resistant hypertension due to primary hyperaldosteronism (Conn’s syndrome).
Adverse effects.
Hyperkalaemia is the major adverse effect of aldosterone antagonists. The risk is greater in patients with renal disease or in those receiving ACE inhibitors, ARBs, β-blockers, NSAIDs, etc.
The other adverse effects include nausea, vomiting, diarrhoea, peptic ulcer, drowsiness, mental confusion, menstrual disturbances, gynaecomastia and decreased libido (antiandrogenic effect).
Drug interaction
- ■
ACE inhibitors × spironolactone: Dangerous hyperkalaemia can occur.
Eplerenone , an aldosterone antagonist , is more selective for MR. Hence, it is less likely to cause gynaecomastia. Its therapeutic uses include hypertension and chronic heart failure.
Amiloride and triamterene (directly acting drugs).
Both are directly acting potassium-sparing diuretics. They directly block Na + channels in the luminal membrane of the cells of late distal tubule and CD. The net effect of these drugs is to increase Na + excretion and retain potassium; hence, these are called potassium-sparing diuretics. They are administered orally. Amiloride inhibits H + secretion in CD – acidosis can occur. Both are low-efficacy diuretics. Amiloride is more potent and longer acting than triamterene. Triamterene is extensively metabolized while amiloride is excreted unchanged in urine.
Uses
- 1.
Potassium-sparing diuretics are used with thiazides/loop diuretics for the treatment of hypertension. The combination therapy increases diuretic and antihypertensive effects of thiazides or loop diuretics. They also correct hypokalaemia due to thiazides/loop diuretics.
- 2.
Amiloride is used for the treatment of lithium-induced nephrogenic DI. It blocks lithium transport through Na + channels in the cells of the CD.
- 3.
Amiloride (aerosol) improves mucociliary clearance in patients with cystic fibrosis.
Adverse effects.
These include hyperkalaemia, nausea, vomiting, diarrhoea, headache, dizziness, muscle cramps, etc.
Various diuretics with their site and mechanism of action are shown in Table 4.1 .
| Diuretics | Site of action | Mechanism of action | Efficacy |
| Acetazolamide | PCT | Carbonic anhydrase inhibitor | Low |
| Loop diuretics | Thick ascending limb of loop of Henle | Inhibit Na + –K + –2Cl − cotransport | High |
| Thiazides | Early distal tubule | Inhibit Na + –Cl − symport | Medium |
| Potassium-sparing diuretics | DT and CD |
| Low |
| Mannitol | Loop of Henle and PCT | Osmotic effect | High |
Diuretic resistance
It is said to occur when the oedema does not respond to a diuretic. Decrease in diuretic response usually due to long-term therapy is common with thiazides; can also occur with loop diuretics. Prolonged use of diuretics causes some pathological changes in the renal tubules, which may lead to development of diuretic resistance.
Diuretic resistance is mainly seen in elderly patients due to age-related declined renal function.
Other factors include chronic renal failure, liver diseases, heart failure and co-administration of diuretic with a NSAID. Resistance can be overcome to some extent by:
- i)
Increasing the dose and frequency of a diuretic
- ii)
Taking diuretic before meal
- iii)
Salt-restricted diet
- iv)
Proper bed rest
- v)
Use of combination of diuretics
- i)
Antidiuretics PH1.24
Vasopressin
Vasopressin (AVP or arginine vasopressin; ADH) is a peptide hormone synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and stored in posterior pituitary.
Both V 1 and V 2 are G-protein–coupled receptors.
Synthetic AVP is a peptide, hence is not effective orally. It is administered by i.v., i.m., s.c. or intranasal routes and has a short duration of action ( Table 4.2 ).
| Drug | Antidiuretic effect (V 2 ) | Vasopressor effect (V 1 ) | Preparations | Duration of action (hours) |
| Arginine vasopressin | 1 | 1 | i.m., i.v., s.c. and nasal | 3–4 |
| Desmopressin | 12 | 0.004 | s.c., i.v., nasal and oral | 8–12 |
| Lypressin | 0.8 | 0.6 | i.m., s.c. and i.v. | 4–6 |
| Terlipressin | - | + | i.v. | 4–6 |
Vasopressin analogues
Desmopressin: It is a selective V 2 receptor agonist and is more potent than vasopressin as an antidiuretic. It has negligible vasoconstrictor action. It is administered by oral, nasal and parenteral routes.
Lypressin: It acts on both V 1 and V 2 receptors. It is less potent but longer acting than vasopressin. It is administered parenterally.
Terlipressin: It is a prodrug of vasopressin with selective V 1 action. It is administered intravenously.
Uses of vasopressin analogues
- 1.
For emergency control of bleeding oesophageal varices: Terlipressin is preferred to vasopressin because it is safer. It acts on V 1 receptor → constricts mesenteric blood vessels → decreases blood flow to portal vessels → reduces pressure in the varices → stops bleeding.
- 2.
Vasopressin may be used before abdominal radiography to expel intestinal gas by acting on V 1 receptor in the intestine.
- 3.
Central (neurogenic) DI – desmopressin (V 2 -mediated action) is the drug of choice (see Table 4.3 ). It is not effective in nephrogenic DI.
- (a)
Haemophilia and von Willebrand’s disease – Desmopressin, administered intravenously, controls bleeding by promoting release of factor VIII and von Willebrand’s factor (by acting on V 2 receptors) .
- (b)
Primary nocturnal enuresis – Administration of desmopressin at bedtime reduces nocturnal urine volume (V 2 -mediated action) .
Table 4.3 ■Types of diabetes insipidus with their treatmentCentral DI (neurogenic or pituitary) Nephrogenic DI (renal DI) - •
There is decreased ADH secretion.
- •
Drug of choice: Desmopressin (since it has more selective action on V 2 receptors).
Route: Intranasal, oral, s.c., i.v.
Duration of therapy: Usually lifelong.
Desmopressin has more selective action on V 2 receptors, hence preferred in central DI. Its action on V 2 receptors in the cells of collecting duct results in a decrease in urine volume.
Other drugs, if patient does not tolerate desmopressin.
Chlorpropamide (oral antidiabetic agent): Increases antidiuretic effect of ADH on kidney.
Carbamazepine (antiepileptic drug): Decreases urine volume in high doses.
Thiazides are also useful in central DI as they decrease urine volume; they act paradoxically in these patients.
- •
ADH levels are normal, but renal tubules (CD) fail to respond to ADH.
- •
Drugs:
Thiazides: Exact mechanism of action of thiazides in DI is not clear. Thiazides probably act by depleting sodium and ECF volume which results in a compensatory increase in proximal tubular reabsorption of Na + and water leading to a decrease in urine volume. Moreover, action of thiazides in the early distal tubule results in the formation of less dilute urine.
Amiloride is the preferred drug for lithium-induced nephrogenic DI as it blocks lithium and sodium entry into the renal epithelial cells.
Indomethacin reduces urine volume in nephrogenic DI by inhibiting renal prostaglandin synthesis.
- (a)
DI is a condition characterized by excretion of large volume of dilute urine either due to decreased secretion of ADH from the neurohypophysis (neurogenic DI) or due to an inadequate renal tubular response to ADH (nephrogenic DI).
Adverse effects of vasopressin analogues
- 1.
Nausea, vomiting, diarrhoea, belching and abdominal cramps.
- 2.
Backache is due to uterine contraction.
- 3.
Vasopressin can precipitate an attack of angina by constricting coronary blood vessels. Hence, it is contraindicated in patients with hypertension and coronary artery disease.
- 4.
Intranasal administration of desmopressin may cause local irritation and ulceration.
- 5.
Fluid retention and hyponatraemia can occur (V 2 -mediated). It should not be given to patients with acute renal failure.
Syndrome of inappropriate antidiuretic hormone (SIADH) secretion
In SIADH, there is impaired water excretion along with hyponatraemia and low plasma osmolality due to inappropriate ADH secretion. The conditions that may be associated with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are head injury, meningitis, brain tumour, pulmonary diseases, etc. The signs and symptoms of SIADH may include anorexia, nausea, vomiting, muscle cramps, lethargy, coma, convulsions and death.
Treatment
- 1.
Restricted water intake
- 2.
Drugs
Demeclocycline is useful in the treatment of SIADH. It inhibits the action of ADH in the CD.
Vasopressin receptor antagonists like conivaptan (V 1a /V 2 ) and tolvaptan (V 2 selective) are useful in the treatment of SIADH. They are nonpeptides which are administered intravenously and orally, respectively.